Process for the preparation of (1s,4s,5s)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one

Abstract

The present invention relates to an improved and industrially advantageous process for the preparation of (1S, 4S, 5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one represented by the following formula (1) which is a key intermediate in the synthesis of edoxaban, a compound that exhibits on inhibitory effect on activated blood coagulation factor X (also referred to as activated factor X or FXa), and is useful as a preventive and/or therapeutic drug for thrombotic diseases. The process includes reacting (1S)-cyclohex-3-ene-1-carboxylic acid of formula (II) with a brominating agent selected from the group consisting of N-bromosuccinimide or 1,3-dibromo-5, 5-dimethylhydantoin in the presence of a base selected from calcium oxide or calcium hydroxide in a solvent selected from the group comprising of dicholoromethane, toluene, tetrahydrofuran, ethyl acetate, hexanes, cyclopentyl methyl ether (CPME) or a misture thereof to get (1S, 4S 5S)-4-bromo-6-oxabicyclo[3.2.1]octan-y-one of formula (1)

1 . A process for producing (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one represented by the following formula (I): 
       
         
           
           
               
               
           
         
       
       comprising treating (1S)-cyclohex-3-ene-1-carboxylic acid represented by the following formula (II): 
       
         
           
           
               
               
           
         
       
       with N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin as brominating agent in the presence of a base selected from calcium oxide or calcium hydroxide in an organic solvent.
 (1) A process for producing (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one, represented by the following formula (I): 
 
       
         
           
           
               
               
           
         
       
       comprising treating (1S)-cyclohex-3-ene-1-carboxylic acid, represented by the following formula (II): 
       
         
           
           
               
               
           
         
       
       with N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin as brominating agent in the presence of a base selected from calcium oxide or calcium hydroxide in a solvent selected from the group consisting of dichloromethane, toluene, tetrahydrofuran, ethyl acetate, hexane, cyclopentyl methyl ether (CPME) or a mixture thereof. 
     
     
         2 . The production process according to  claim 1 , wherein the brominating agent is N-bromosuccinimide. 
     
     
         3 . A process for producing tert-butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate: 
       the method using (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (I) produced by a method according to  claim 1  and comprising the following steps a) and b):
 a) treating (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (I) produced by a production process according to (1) with an aqueous solution of dimethylamine followed by reacting with aqueous ammonia, subsequently with a di-tert-butyl dicarbonate and further with methanesulfonyl chloride to obtain methanesulfonic acid (1R,2R,4S)-2-tert-butoxycarbonylamino-4-dimethylcarbamoyl-cyclohexyl ester, 
 b) treating the methanesulfonic acid (1R,2R,4S)-2-tert-butoxycarbonylamino-4-dimethylcarbamoyl-cyclohexyl ester with sodium azide, followed by subjecting the resultant compound to hydrogenolysis in the presence of Palladium-Carbon and ammonium formate and reacting the resultant compound with oxalic acid to obtain tert-Butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate. 
 
     
     
         4 . A process for producing N 1 -(5-chloropyridin-2-yl)-N 2 -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5, 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl) ethanediamide p-toluenesulfonate monohydrate: 
       the method using (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (I) produced by a method according to  claim 1  and comprising the following steps a) to e):
 a) treating (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (I) produced by a production process according to (1) with an aqueous solution of dimethylamine followed by reacting with aqueous ammonia, subsequently with di-tert-butyl dicarbonate and further with methanesulfonyl chloride to obtain methanesulfonic acid (1R,2R,4S)-2-tert-butoxycarbonylamino-4-dimethylcarbamoyl-cyclohexyl ester, 
 b) treating the methanesulfonic acid (1R,2R,4S)-2-tert-butoxycarbonylamino-4-dimethylcarbamoyl-cyclohexyl ester with sodium azide, followed by subjecting the resultant compound to hydrogenolysis in the presence of Palladium-Carbon and ammonium formate and reacting the resultant compound with oxalic acid to obtain tert-Butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate, 
 c) reacting the tert-Butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate with ethyl[5-chloropyridin-2-yl]amino](oxo)acetate hydrochloride in the presence of triethylamine to obtain tert-Butyl[(1R,2S,5S)-2-({[(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate, 
 d) deprotecting the tert-Butoxycarbonyl group from the tert-Butyl[(1R,2S,5S)-2-({[(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate by using methanesulphonic acid followed by reacting the deprotected compound with 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride or its activated ester to obtain N 1 -(5-chloropyridin-2-yl)-N 2 -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5, 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl) ethanediamide, 
 e) treating the N 1 -(5-chloropyridin-2-yl)-N 2 -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5, 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl) ethanediamide with p-toluenesulfonic acid in aqueous ethanol to obtain N 1 -(5-chloropyridin-2-yl)-N 2 -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5, 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl) ethanediamide p-toluenesulfonate monohydrate.